JP3221955B2 - 3,4'-dideoxydesmycosin - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to the antibiotic 3,4'-dideoxydesmycosin.

[0002]

2. Description of the Related Art As a macrolide antibiotic, josamycin and erythromycin are widely used clinically. However, in recent years, macrolide-resistant bacteria exhibiting resistance to these macrolide antibiotics have been increasing, and development of new antibiotics has been desired.

[0003] Desmycosin is a biosynthetic intermediate of tylosin (Antimicrobial Agents and Chemotherapy, Mar. 197).
7, p455-461) and hydrolysis of tylosin (Anti
biotics and Chemotherapy, vol. 11, p328-334, 1961)
Can be easily obtained by: However, since this substance does not show sufficient antibacterial activity, it has never been applied as a therapeutic agent. The present inventors have synthesized various derivatives of desmycosin and studied the antibacterial activity thereof. As a novel antibiotic having a strong antibacterial activity even against macroylide-resistant bacteria, 3,4 ′.
-Dideoxydesmycosin was found, and the present invention was completed.

[0004]

SUMMARY OF THE INVENTION The 3,4'-dideoxydesmycosin of the present invention is a novel antibiotic represented by the following formula.

[0005]

Embedded image An example of the method for producing 3,4'-dideoxydesmycosin of the present invention is shown in the following production scheme, but the method for producing 3,4'-dideoxydesmycosin of the present invention is limited to these methods. Never. In the scheme, A represents a protected carbonyl group, B represents a protected aldehyde group, prot represents a protecting group, X represents a halogen atom, R ¹ independently represents a sulfonic acid residue, and R ²
Represents a lower alkanoyl group. According to the method of the following scheme, from the readily available tylosin,
4'-dideoxydesmycosin can be efficiently and efficiently produced.

[0006]

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[0007]

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[0008]

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[0009]

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[0010]

Embedded image The mycaminosyltylonolide derivative represented by the formula (IV) can be obtained by treating tylosin with an acid anhydride by treating the tylosin with an acid anhydride, for example, by the method described in Journal of Antibiotics (35, 661, 1982). O-acyltyrosine (I
The compound (I) can be obtained, and the compound can be protected by a suitable protecting group. As the protecting group for the carbonyl group or aldehyde group represented by A or B, those which are obvious to those skilled in the art may be used. For example, dimethyl acetal (dimethyl ketal), diethyl acetal (diethyl ketal), diethyl thiol Acetal (or thioacetal) such as acetal (diethylthioketal), ethylene acetal (ethylene ketal), and propylene acetal (propylene ketal), or ketal (or thioketal) can be used. Examples of the lower alkanoyl group represented by R ² include a straight-chain or branched group having 1 to 6 carbon atoms such as a formyl group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, a pivaloyl group, and a hexanoyl group. Alkanoyl groups. In addition, protecting groups for hydroxyl groups
As the (prot), any one which is obvious to those skilled in the art may be used. For example, t-butyldimethylsilyl, dimethylsexylsilyl, trimethylsilyl, triethylsilyl, tri (t-butyl) silyl and the like can be used. Alkylsilyl, trityl, tetrahydropyranyl, tetrahydrofuranyl, lower alkanoyl such as allyl, acetyl, benzoyl, benzyl, methoxymethyl, benzyloxycarbonyl and the like can be used.

By reacting the above-mentioned mycaminosyltylonolide derivative represented by the formula (IV) with a sulfonylating agent such as a substituted sulfonic acid or a reactive derivative thereof, the hydroxyl groups at the 3-position and the 4'-position are converted. Sulfonylated formula
Compound (V) can be obtained. As the substituted sulfonic acid, benzyl sulfonic acid, benzyl sulfonic acid having 1 to 3 substituents such as methyl group and ethyl group on a benzene ring, and the like can be preferably used. As the reactive derivative of the substituted sulfonic acid, a halide such as chloride or bromide or an acid anhydride may be used. For example, when the reaction is carried out using benzylsulfonyl chloride, the 3- and 4'-positions can be efficiently sulfonylated. The sulfonylation reaction may be usually performed in an organic solvent at a temperature of −40 ° C. to + 50 ° C. As the solvent, for example, acetonitrile, acetone, dimethyl sulfoxide, dioxane, toluene, ethyl acetate and the like may be used. Pyridine, 4-dimethylaminopyridine, triethylamine and the like may be used as the basic catalyst and / or solvent.

The sulfonic acid residue represented by R ¹ includes, for example, mesyl, ethanesulfonyl, propylsulfonyl, isopropylsulfonyl, benzenesulfonyl, tosyl, benzylsulfonyl and the like. Specifically, when -OR ¹ is represented by -OSO ₂ R ³ , R ³ is, for example, a lower alkyl group, a trifluoromethyl group, a 2-oxo-10-bornanyl group, a substituted or unsubstituted allyl group, or Represents a substituted or unsubstituted aralkyl group. Examples of the lower alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, a 1-methylbutyl group, a 2-methylbutyl group, and a neopentyl group. it can. Examples of the substituted or unsubstituted allyl group include a phenyl group, p-methoxyphenyl group, p-nitrophenyl group, p-fluorophenyl group, p, o-difluorophenyl group, p-chlorophenyl group, m-chlorophenyl group, o -Chlorophenyl group, o, p-dichlorophenyl group, p-bromophenyl group, p-methylphenyl group, m-methylphenyl group,
An o, p-dimethylphenyl group, an m, p-dimethylphenyl group, a naphthyl group and the like can be mentioned. As a substituted or unsubstituted aralkyl group, benzyl group, p-nitrobenzyl group, o, p-dinitrobenzyl group, p-chlorobenzyl group, m-
Examples thereof include a chlorobenzyl group, a p-methylbenzyl group, an m-methylbenzyl group, an o-methylbenzyl group, an o, p-dimethylbenzyl group, a p-methoxybenzyl group, and a p-fluorobenzyl group.

The compound of the above formula (V) is, for example, acetone,
By reacting with an halogenating agent such as sodium iodide, potassium iodide, lithium bromide, tetrabutylammonium bromide or tetrabutylammonium chloride in an inert solvent such as 2-butanone or dimethylformamide, 4 'is selectively formed. Halogenated formula (V
The compound represented by I) can be obtained. The halogen atom represented by X may be, for example, any of a chlorine atom, a bromine atom and an iodine atom. Usually, the halogenation reaction may be performed at -30 to 100 ° C depending on the type of the sulfonyl residue. Depending on the halogenation conditions, the 2,3 position or 3,4 position
Some compounds having a double bond at the position may be formed, but these compounds may be used as a starting compound in the next step.

By reducing the compound of the above formula (VI) under alkaline conditions, the 3-position and the 4'-position are simultaneously hydrogen-substituted to give the 3,4'-dideoxydesmycoside of the formula (VII). Syn derivatives can be produced. The reaction is carried out, for example, in a solvent inert to the reaction in the presence of a catalyst in the presence of a catalyst.
It is carried out by catalytically reducing the compound represented by (VI). As the base used for forming the alkaline conditions, sodium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate and the like, preferably potassium carbonate can be used. These bases are generally used in a proportion of 2 to 5 mol based on the compound represented by the formula (VI) as a substrate. Examples of the catalyst used for the catalytic reduction include platinum, palladium, Raney nickel and the like, preferably Raney nickel. The amount of the catalyst to be used varies depending on the type of the catalyst, but generally, it may be used at a ratio of 1/10 to 1 with respect to the compound represented by the formula (VI) as a substrate. Examples of the inert solvent include solvents such as methanol, ethanol, and tetrahydrofuran. In carrying out the catalytic reduction, the reaction may be carried out at a hydrogen addition pressure of normal pressure to 5 kg / cm ² and a reaction temperature of, for example, under cooling to room temperature, preferably -10 to 30 ° C. These conditions vary depending on the type of the starting compound and the catalyst, but are appropriately selected by those skilled in the art.

According to the above process, the 3-position and the 4'-position of the compound represented by the formula (VI) can be simultaneously hydrogen-substituted,
Thus, the 3,4'-dideoxydesmycosin derivative represented by the formula (VII) can be obtained from the compound of the formula (VI) in one step and in a high yield (about 80%). The compound of formula (VII) thus obtained can be converted to 3,4'-dideoxydesmycosin of the present invention or a salt thereof by removing the protecting group according to a conventional method. The removal of the protecting group may be usually performed by treating with a mineral acid such as hydrochloric acid or sulfuric acid in the presence of water, or by treating with an organic acid such as acetic acid, trifluoroacetic acid, or trichloroacetic acid. It is also carried out by using an arylsulfonic acid such as p-toluenesulfonic acid, an alkylsulfonic acid such as methanesulfonic acid, or the like in a solvent such as dioxane, dimethylformamide, dimethylsulfoxide, or acetonitrile, and treating at room temperature to under heating. Can be.

[0016] 3,4'-Dideoxydesmycosin obtained by the method of the present invention is a substance having an antibacterial activity against a wide range of microorganisms belonging to Gram-positive and -negative, and particularly, erythromycin and josamycin. It has excellent antibacterial activity against resistant macrolide-resistant bacteria, and is therefore useful as an antibacterial agent. 3 of the present invention
Table 1 below shows the results obtained by measuring the minimum growth element concentration (MIC) of 4'-dideoxydesmycosin against various bacteria according to the standard method of the Japan Society for Chemotherapy.

[0017]

[Table 1] Test bacteria A EM JM ─────────────────────────────────── Bacillus subtilis 0.05 0.05 0.20 Bacillus subtilis ATCC6633 Micrococcus luteus <0.006 <0.006 0.012 Micrococcus luteus ATCC9341 Staphylococcus aureus 0.024 0.024 0.05 Staphylococcus aureus 209P Staphylococcus aureus 0.20 0.10 1.56 Staphylococcus aureus Smith staphylocicus Staphylococcus aureus 0.10 100 0.78 Staphylococcus aureus MS8710 ^* Staphylococcus aureus 0.05> 100 0.20 Staphylococcus aureus MS11593 ^* Staphylococcus aureus 0.05>100> 100 Staphylococcus aureus MS11598 * Staphylococcus aureus 0.39> 100 100 Staphylococcus aureus MS11612 ^* Staphylococca Aureus 0.78>100> 100 Staphylococcus aureus KS24 * ─────────────────────────────────── A: 3, 4'-dideoxydesmycosin; EM: erythromycin; JM: josamycin * Test bacteria indicated by * are macrolide antibiotic resistant clinical isolates. The 3,4'-dideoxydesmycosin of the present invention is preferably incorporated into a pharmaceutical composition as an active ingredient and administered to a patient as a therapeutic agent for infectious diseases. 3, 4 'of the present invention
-Pharmaceutical compositions containing dideoxydesmycosin as an active ingredient are usually capsules, tablets, fine granules, granules,
It is prepared as an oral preparation such as a powder, a syrup, or an injection, a suppository, an eye drop, an eye ointment, an ear drop, or a skin. These pharmaceutical compositions can be manufactured by a conventional method, and if necessary, medicines such as disintegrants, binders, lubricants, coating agents, bases, solubilizing agents, tonicity agents, stabilizers, pH regulators, etc. Well-known additives that are physically and pharmaceutically acceptable may be added. The dose of the 3,4'-dideoxydesmycosin of the present invention may be variously changed depending on the administration route, the type of the bacterium causing the infection, and the like.
It may be administered once or several times at about 1000 mg.

[0018]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples. Production of 2'-O-acetyldesmycosin 9,20-bis (ethylene acetal)

[0019]

Embedded image 23.7 g of 2'-O-acetyltylosin was added to toluene 10
0 ml, followed by 12.36 g of ethyl orthoformate (83.
5 mmol), 12.95 g (208.8 mm) of ethylene glycol
ol) and 6.30 g (27.1 mmol) of camphorsulfonic acid
Was added to give a homogeneous solution. After stirring this solution at 50 ° C. for 2 hours, the reaction mixture was mixed with 100 ml of 5% aqueous sodium bicarbonate, 100 ml of water,
Washed with 10% saline. The organic layer was dried over anhydrous sodium sulfate and then dried under reduced pressure to obtain toluene / acetone (1/1).
1) 20.20 g of the title compound positive for sulfuric acid coloring with an Rf value of 0.49 was obtained by silica gel TLC developed.

UV (MeOH) λmax; 235 nm IR (KBr) νmax; 3470, 2975, 2938, 2882, 1746, 1236, 1169, 1
084,961 cm ^-1 NMR (CDCl ₃ ); representing only the main peak δ; 0.78 (3H, bs, H-18), 0.93 (3H, t, J = 7.3 Hz, H-17), 1.01
(3H, d, J = 6.6Hz, H-21), 1.26 (3H, d, J = 6.2Hz, H-6 ″), 1.32
(3H, d, J = 6.2Hz, H-6 '), 1.70 (3H, s, H-22), 2.01 (3H, s, O
COCH ₃ -2 '), 2.39 [6H, s, N (CH ₃ ) ₂ -3'], 3.05 (1H, t, J = 9.5
Hz, H-4 '), 3.18 (1H, bd, J = 7.0Hz, H-4''), 3.49 (3H, s, O
CH ₃ -2 ″), 3.62 (3H, s, OCH ₃ -3 ″), 4.55 (1H, d, J = 8.1Hz, H-1
″), 4.64 (1H, br, H-1 ′), 4.96 (1H, m, H-20), 4.96 (1H,
m, H-15), 5.03 (1H, dd, J = 10.6 & 7.7Hz, H-2 '), 5.42 (1H,
d, J = 10.6Hz, H-13), 5.64 (1H, d, J = 15.8Hz, H-10), 6.37 (1
H, d, J = 15.8Hz, H-11) FAB-MS; Production of 902 (M + H) ⁺ 2'-O-acetyl-4 "-O-trimethylsilyldesmycosin 9,20-bis (ethylene acetal)

[0021]

Embedded image 18.9 g (20.9 mmol) of 2'-O-acetyldesmycosin 9,20-bis (ethylene acetal) was dissolved in 94 ml of toluene, 2.52 ml (31.2 mmol) of pyridine was added, and the mixture was cooled to -5 ° C. . To this solution, 3.42 ml (27 mmol) of trimethylsilane chloride was added dropwise, and reacted at the same temperature for 80 minutes. The reaction solution was washed with 150 ml of 5% aqueous sodium bicarbonate solution and 150 ml of 10% saline solution and dried over anhydrous sodium sulfate. When the organic layer is concentrated under reduced pressure, toluene / acetone (1/1)
20.64 g of the title compound having a sulfuric acid coloration positive at an Rf value of 0.57 was obtained by silica gel TLC using an eluant.

UV (MeOH) λmax; 235 nm IR (KBr) νmax; 3520,2973,2884,1748,1713,1373,1236,1
171,1100,966,882,841cm ^-1 NMR (CDCl ₃ ); representing only the main peak δ; 0.17 [9H, s, Si (CH ₃ ) ₃ ], 0.77 (3H, bs, H-18), 0.91 (3H,
t, J = 7.3Hz, H-17), 1.01 (3H, d, J = 6.6Hz, H-21), 1.18 (3H,
d, J = 6.2Hz, H-6 ″), 1.32 (3H, d, J = 5.9Hz, H-6 ′), 1.69 (3
H, d, J = 0.7Hz, H-22), 2.01 (3H, s, OCOCH ₃ -2 '), 2.38 [6H,
s, N (CH ₃ ) ₂ -3 '], 2.59 (1H, t, J = 10.3Hz, H-3'), 3.05 (1
H, t, J = 9.9Hz, H-4 '), 3.28 (1H, dd, J = 9.2 & 2.6Hz, H-
4 ″), 3.49 (3H, s, OCH ₃ -2 ″), 3.60 (3H, s, OCH ₃ -3 ″), 4.
59 (1H, d, J = 7.7Hz, H-1 ″), 4.64 (1H, br, H-1 ′), 4.95 (1H,
m, H-20), 4.96 (1H, m, H-15), 5.03 (1H, dd, J = 10.6 & 7.7Hz,
H-2 '), 5.42 (1H, d, J = 10.6Hz, H-13), 5.62 (1H, d, J = 15.8H
z, H-10), 6.36 (1H, d, J = 15.8Hz, H-11) FAB-MS; 974 (M + H) ⁺ 2'-O-acetyl-3,4'-di-O-methanesulfonyl- 4 "-O-trimethylsilyl-desmycosin
Production of 9,20-bis (ethylene acetal)

[0023]

Embedded image 2'-O-acetyl-4 "-O-trimethylsilyldesmycosin 9,20-bis (ethylene acetal) 1
After dissolving 0.07 g (10.3 mmol) in 50 ml of toluene, 7.20 ml (51.7 mmol) of triethylamine was added and the mixture was cooled to -15 ° C. 2.8 ml of methanesulfonyl chloride was added to this solution.
(36.2 mmol) was added and reacted at -10 ° C for 1 hour. 40 ml of toluene was added to the reaction solution, and the organic layer was washed with 80 m of water.
After washing with 40 ml of 5% aqueous sodium bicarbonate and 40 ml of 10% saline, the mixture was dried over anhydrous sodium sulfate. The organic layer was dried under reduced pressure to obtain silica gel T developed with toluene / acetone (3/1).
The title compound positive for sulfuric acid coloring with an Rf value of 0.55 was determined by LC.
94 g were obtained. Since this compound was unstable, it was immediately subjected to the next reaction.

NMR (CDCl ₃ ); representing only the main peak δ; 0.16 [9H, s, Si (CH ₃ ) ₃ ], 0.88 (3H, d, J = 7.3 Hz, H-18), 0.
92 (3H, t, J = 7.3Hz, H-17), 1.02 (3H, d, J = 6.6Hz, H-21), 1.1
8 (3H, d, J = 6.2Hz, H-6 ″), 1.35 (3H, d, J = 5.9Hz, H-6 ′),
1.69 (3H, d, J = 0.7Hz, H-22), 2.04 (3H, s, OCOCH ₃ -2 '), 2.
39 [6H, s, N ( CH 3) 2 -3 '], 2.93 (1H, t, J = 10.3Hz, H-3'), 3.
10 (3H, s, OMs), 3.14 (3H, s, OMs), 3.28 (1H, dd, J = 9.5 & 2.6H
z, H-4 ″), 3.47 (3H, s, OCH ₃ -2 ″), 3.59 (3H, s, OCH ₃ -3 ″),
4.22 (1H, t, J = 9.9Hz, H-4 '), 4.57 (1H, d, J = 7.7Hz, H-1
″), 4.60 (1H, br, H-1 ′), 4.75 (1H, br, H-3), 4.93 (1H,
m, H-15), 4.96 (1H, m, H-20), 5.03 (1H, dd, J = 10.3 & 8.0Hz,
H-2 '), 5.47 (1H, d, J = 11.0Hz, H-13), 5.54 (1H, d, J = 15.8
Hz, H-10), 6.34 (1H, d, J = 15.8 Hz, H-11) FAB-MS; 1130 (M + H) ⁺ 2'-O-acetyl-4'-deoxy-4'-iodo-
Production of 3-O-methanesulfonyl-4 "-O-trimethylsilyldesmycosin 9,20-bis (ethylene acetal)

[0025]

Embedded image 2'-O-acetyl-3,4'-di-O-methanesulfonyl-4 "-O-trimethylsilyldesmycosin
12.20 g of 9,20-bis (ethylene acetal) (1
1.5 mmol) was dissolved in 60 ml of methyl ethyl ketone, and 2.58 g (17.2 mmol) of sodium iodide was added thereto.
The reaction was performed at 5 ° C. for 1 hour. After cooling the reaction solution to room temperature, the precipitate was separated by filtration and the precipitate was washed with 5 ml of toluene. The washing solution and the mother liquor are combined, concentrated under reduced pressure, and toluene 60 ml and water 60 ml.
Was added and liquid separation was performed. The organic layer was washed with 10% sodium thiosulfate (40 ml) and water (40 ml), dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure.
1) By silica gel TLC developed, 10.73 g of the title compound positive for sulfuric acid coloring with an Rf value of 0.51 was obtained.

UV (MeOH) λmax; 235 nm IR (KBr) νmax; 3443,2973,2940,2886,1746,1360,1233,1
173,1101,1049,966,909,882,843 cm ^-1 NMR (CDCl ₃ ); representing only the main peak δ; 0.16 [9H, s, Si (CH ₃ ) ₃ ], 0.89 (3H, d, J = 7.3 Hz, H- 18), 0.
92 (3H, t, J = 7.3Hz, H-17), 1.02 (3H, d, J = 7.0Hz, H-21), 1.1
8 (3H, d, J = 6.2Hz, H-6 ″), 1.51 (3H, d, J = 5.9Hz, H-6
'), 1.69 (3H, d, J = 0.7Hz, H-22), 2.02 (3H, s, OCOCH ₃ -2
'), 2.42 [6H, s , N (CH 3) 2 -3'], 3.12 (3H, s, OMs-3), 3.
47 (3H, s, OCH ₃ -2 ″), 3.59 (3H, s, OCH ₃ -3 ″), 4.57 (1H, d,
J = 8.1Hz, H-1 ″), 4.57 (1H, br, H-1 ′), 4.77 (1H, br, H-3),
4.91 (1H, dd, J = 9.9 & 7.3Hz, H-2 '), 4.93 (1H, m, H-15), 4.
98 (1H, br, H-20), 5.47 (1H, d, J = 10.6Hz, H-13), 5.54 (1H,
d, J = 15.8Hz, H-10), 6.34 (1H, d, J = 15.8Hz, H-11) FAB-MS; 1162 (M + H) ⁺ 2'-O-acetyl-3,4'-dideoxydes Production of mycosin 9,20-bis (ethylene acetal)

[0027]

Embedded image 2'-O-acetyl-4'-deoxy-4'-iodo-
3-O-methanesulfonyl-4 ″ -O-trimethylsilyldesmycosin 9.70 g (9.2 mmol) of 9,20-bis (ethylene acetal) was dissolved in 50 ml of methanol, and 3.82 g (27.6 mmol) of potassium carbonate was dissolved. Subsequently, a suspension of Raney nickel (Kawaken Fine Chemicals NDT-65, wet weight: 6.4 g (5 ml)) in 8 ml of methanol was added, and catalytic reduction was carried out at a hydrogen pressure of 3 kg / cm ^{2 for} 2 hours. After filtration, the mother liquor was concentrated under reduced pressure, 100 ml of ethyl acetate and 100 ml of water were added to the residue, and the organic layer was washed with 100 ml of 20% saline and concentrated under reduced pressure. After adding 1.5 hours at room temperature,
The mixture was washed with 30 ml of a 20% aqueous sodium bicarbonate solution and 30 ml of a 20% saline solution. The organic layer was dried over anhydrous sodium sulfate and then dried under reduced pressure to obtain silica gel T developed with chloroform / methanol (10/1).
The title compound positive for sulfuric acid coloration with an Rf value of 0.44 by LC was 7.4.
6 g were obtained.

UV (MeOH) λmax; 235 nm IR (KBr) νmax; 3476,2973,2938,2882,1744,1373,1238,1
167, 1061, 961 cm ^-1 NMR (CDCl ₃ ); representing only the main peak δ; 0.82 (3H, bd, J = 5.5 Hz, H-18), 0.92 (3H, t, J = 7.3 Hz, H-1
7), 1.00 (3H, d, J = 6.6Hz, H-21), 1.23 (3H, d, J = 6.2Hz, H-
6 ′), 1.26 (3H, d, J = 6.2Hz, H-6 ″), 1.35 (1H, m, H-4′a),
1.71 (1H, m, H-4′b), 1.73 (3H, d, J = 1.1Hz, H-22), 2.04
_{(3H, s, OCOCH 3 -2} '), 2.26 [6H, s, N (CH 3) 2 -3'], 2.68 (1
H, ddd, J = 12.3 & 10.4 & 4.4Hz, H-3 ′), 3.18 (1H, br, H-4 ″),
3.48 (3H, s, OCH ₃ -2 ″), 3.61 (3H, s, OCH ₃ -3 ″), 4.31 (1
H, d, J = 7.7Hz, H-1 ″), 4.55 (1H, d, J = 7.7Hz, H-1 ″), 4.80
(1H, dd, J = 10.4 & 7.7Hz, H-2 '), 4.90 (1H, m, H-15), 4.95
(1H, bt, J = 5.1Hz, H-20), 5.42 (1H, d, J = 10.6Hz, H-13), 5.6
2 (1H, d, J = 15.8Hz, H-10), 6.36 (1H, d, J = 15.8Hz, H-11) FAB-MS; 870 (M + H) ⁺ 3,4'-dideoxydesmycosin Production 2'-O-acetyl-3,4'-dideoxydesmycosin 9,20-bis (ethylene acetal) 211 mg
Was dissolved in 0.5 ml of acetone, 2.5 ml of 0.1N hydrochloric acid was added, and the mixture was reacted at 50 ° C. for 4 hours. 5 ml of chloroform was added, and the organic layer was washed with 3 ml of 5% aqueous sodium bicarbonate and 5 ml of 10% saline. The organic layer was dried over anhydrous sodium sulfate and then dried under reduced pressure to obtain 177 mg of a deacetalized product. This compound was dissolved in 1.77 ml of methanol, reacted at 60 ° C. for 1.5 hours, and left at room temperature for 16 hours. After the reaction solution was evaporated to dryness under reduced pressure, the residue was dissolved in a small amount of chloroform, adsorbed on a silica gel (12 g) column, and eluted with chloroform and chloroform / methanol (10/1). An Rf value of 0 was determined by silica gel TLC developed with chloroform / methanol (5/1).
The fractions exhibiting sulfuric acid coloration in 36 were collected and solidified under reduced pressure to obtain 70 mg of the title compound.

UV (MeOH) λmax; 283 nm IR (KBr) νmax; 3457, 2969, 2936, 2880, 1726, 1678, 1593, 1
456,1381,1314,1167,1078,986cm ^-1 NMR (CDCl ₃ ); representing only the main peak δ; 0.93 (3H, t, J = 7.3 Hz, H-17), 1.03 (3H, d, J = 6.6Hz, H-1
8), 1.20 (3H, d, J = 6.2Hz, H-6 '), 1.21 (3H, d, J = 6.6Hz, H-2
1), 1.25 (1H, m, H-4'a), 1.26 (1H, d, J = 6.2Hz, H-6 ″), 1.3
0 (1H, m, H-3a), 1.41 (1H, m, H-3b), 1.71 (1H, m, H-4'b), 1.
81 (3H, d, J = 1.1Hz, H-22), 2.32 [6H, s, N (CH 3) 2 -3 '], 3.4
8 (3H, s, OCH ₃ -2 ″), 3.61 (3H, s, OCH ₃ -3 ″), 4.19 (1H, d, J
= 7.3Hz, H-1 '), 4.56 (1H, d, J = 7.7Hz, H-1''), 4.91 (1H, m,
H-15), 5.89 (1H, d, J = 10.3Hz, H-13), 6.32 (1H, d, J = 15.2H
z, H-10), 7.31 (1H, d, J = 15.2Hz, H-11), 9.69 (1H, s, H-20) FAB-MS; 740 (M + H) ⁺

[0030]

According to the present invention, 3,4'-dideoxydesmycosin useful as an antibacterial agent is provided. Since the compound has a strong antibacterial action against macrolide antibiotic-resistant bacteria resistant to erythromycin, josamycin and the like, it is useful as a therapeutic agent for infectious diseases.

──────────────────────────────────────────────────続 き Continuing from the front page (72) Inventor Hiroshi Nishida 568, Tsukui, Yukusuka City, Kanagawa Prefecture Green Heights 11-3-503 (72) Inventor Rokuro Okamoto 2-18 Hanagi, Fujisawa City, Kanagawa Prefecture (72) Inventor Tomio Takeuchi Tokyo 5-1-11 701-A, Higashi-Gotanda, Shinagawa-ku (56) References JP-A-57-42698 (JP, A) (58) Fields studied (Int. Cl. ⁷ , DB name) C07H 17/00- 17/08 CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. The following formula: 3,4'-dideoxydesmycosin represented by